Etiology
The etiology is most often autoimmune. Risk factors for development of autoimmunity include
Genetic factors include the AIRE gene mutation, which is causative of type 1, and certain human leukocyte antigen (HLA) subtypes, which are important in the development of types 2 and 3.
Environmental triggers include viral infections, dietary factors, and other as yet unknown exposures.
Immune check point inhibitors, which are used to treat some types of cancer and are associated with autoimmune endocrine disease, including hypophysitis, thyroid disease, primary adrenal insufficiency, and type 1 diabetes mellitus, are a trigger.
Pathophysiology
The underlying autoimmune reaction involves autoantibodies against endocrine tissues, cell-mediated autoimmunity, or both and leads to inflammation, lymphocytic infiltration, and partial or complete gland destruction. More than one endocrine gland is involved, although clinical manifestations are not always simultaneous. The autoimmune reaction and associated immune system dysfunction can also damage nonendocrine tissues.
Classification
Three patterns of autoimmune failure have been described in polyglandular deficiency syndrome (see table Characteristics of Polyglandular Deficiency Syndromes), which likely reflect different autoimmune abnormalities. Some experts combine type 2 and type 3 into a single group. The prevalence of type 2 is about 1 per 1000 whereas type 1 occurs in about 1 per 100,000 (1).
Type 1 polyglandular deficiency
Type 1 polyglandular deficiency, also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), usually begins in childhood. It is caused by mutations in the AIRE gene and is inherited in an autosomal recessive pattern. It is defined by the presence of ≥ 2 of the following:
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Adrenal insufficiency (Addison disease)
Candidiasis is usually the initial clinical manifestation, most often occurring in patients < 5 years of age. Hypoparathyroidism occurs next, usually in patients < 10 years. Lastly, adrenal insufficiency occurs in patients < 15 years. Accompanying endocrine and nonendocrine disorders (see table Characteristics of Polyglandular Deficiency Syndromes) continue to appear at least until patients are about age 40.
Type 2 polyglandular deficiency
Type 2 polyglandular deficiency, also known as Schmidt syndrome, usually occurs in adults; peak incidence is age 30. It occurs 3 times more often in women. It is associated with certain human leukocyte antigen (HLA) genotypes and exhibits polygenic inheritance. It typically manifests with the following:
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Type 1 diabetes mellitus (autoimmune etiology)
More rare features may also be present (see table Characteristics of Polyglandular Deficiency Syndromes).
Type 3 polyglandular deficiency
Type 3 is glandular failure that usually occurs in adults, particularly middle-aged women. It also is associated with certain HLA genotypes and exhibits polygenic inheritance. It is characterized by
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At least one of a variety of other disorders (see table Characteristics of Polyglandular Deficiency Syndromes)
Type 3 does not involve the adrenal cortex.
Characteristics of Polyglandular Deficiency Syndromes
Characteristic |
Type 1 |
Type 2 |
Type 3 |
Demographics |
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|
Age at onset |
Childhood (3–5 years) |
Adulthood (peak 30 years) |
Adulthood (particularly middle-aged women) |
|
Female:male |
4:3 |
3:1 |
Data not available |
Genetics |
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|
Human leukocyte antigen (HLA) types |
May influence the development of specific components of the disorder |
Primarily, B8, DW3, DR3, DR4 Others in specific disorders |
DR3, DR4 |
|
Inheritance |
Autosomal recessive mutation of the AIRE gene |
Polygenic |
Polygenic |
Glands affected |
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|
Common |
Parathyroid Adrenals Gonads |
Adrenals Thyroid Pancreas |
Thyroid Pancreas |
|
Less common |
Pancreas Thyroid |
Gonads |
Variable |
Clinical |
|||
|
Adrenal insufficiency (Addison disease) |
73–100% |
100% |
Not present |
|
26–32% |
Not present |
* |
|
|
Rare |
* |
* |
|
|
Chronic active hepatitis |
20% |
Not present |
Data not available |
|
73–97% |
Not present |
Data not available |
|
|
Diabetes mellitus (type 1) |
2–30% |
52% |
* |
|
Gonadal failure |
In men, 15–25% In women, 60% |
3.5% |
* |
|
76–99% |
Not present |
Not present |
|
|
22–24% |
Not present |
Data not available |
|
|
Not present |
* |
* |
|
|
13–30% |
< 1% |
* |
|
|
Not present |
Not present |
* |
|
|
Thyroid disorders† |
10–11% |
69% |
100% |
|
4–30% |
5–50% |
N/A |
|
|
* Associated; incidence uncertain. |
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|
† Usually chronic lymphocytic thyroiditis but also includes Graves disease. |
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|
Data from Husebye ES, Perheentupa J, Rautemaa R, Kampe O: Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type 1. Journal of Internal Medicine 265: 519–529, 2009; Trence DL, Morley JE, Handwerger BS: Polyglandular autoimmune syndromes. American Journal of Medicine 77(1):107–116, 1984; Leshin M: Polyglandular autoimmune syndromes. American Journal of Medical Sciences 290(2):77–88, 1985; Dittmar M, Kahaly GJ: Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up.Journal of Clinical Endocrinology and Metabolism 88:2983–2992, 2003; and Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. New England Journal of Medicine 350:2068–2079, 2004. |
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Classification reference
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1. Husebye ES, Anderson MS, Kampe O: Autoimmune polyendocrine syndromes. New England Journal of Medicine 378:1132–1141, 2018. doi: 10.1056/NEJMra1713301
Symptoms and Signs
The clinical appearance of patients with polyglandular deficiency syndromes is the sum of the individual endocrine deficiencies and associated nonendocrine disorders; their symptoms and signs are discussed elsewhere in THE MANUAL. The deficiencies do not always appear at the same time and may require a period of years to manifest; in such cases they do not follow a particular sequence.
Diagnosis
Diagnosis of polyglandular deficiency syndromes is suggested clinically and confirmed by detecting deficient hormone levels. Other causes of multiple endocrine deficiencies include hypothalamic-pituitary dysfunction and coincidental endocrine dysfunction due to separate causes (eg, tuberculous hypoadrenalism and nonautoimmune hypothyroidism in the same patient).
Type 1 polyglandular deficiency is associated with autoantibodies against type 1 interferons, and presence of these antibodies suggests the diagnosis, which can be confirmed by mutational analysis of the AIRE gene. Detecting autoantibodies to each affected glandular tissue can help differentiate polyglandular deficiency syndromes from the other causes, and elevated levels of pituitary tropic hormones (eg, thyroid-stimulating hormone) suggest the hypothalamic-pituitary axis is intact (although some patients with type 2 polyglandular deficiency syndrome have hypothalamic-pituitary insufficiency).
Because decades may pass before the appearance of all manifestations, lifelong follow-up is prudent; unrecognized hypoparathyroidism or adrenal insufficiency can be life threatening.
Relatives should be made aware of the diagnosis and screened when appropriate. A trial following relatives of patients with type 1 diabetes for development of autoimmunity found antibodies associated with type 1 diabetes, celiac disease, and/or thyroid disease in 21.5% of subjects (1).
Diagnosis reference
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1. Winkler C, Jolink M, Knopff A, et al: Age, HLA, and sex define a marked risk of organ-specific autoimmunity in first-degree relatives of patients with type 1 diabetes. Diabetes Care 42:1684–1691, 2019. doi: 10.2337/dc19-0315
Treatment
Treatment of the various individual glandular deficiencies is discussed elsewhere in THE MANUAL; the treatment of multiple deficiencies can be more complex than treatment of an isolated endocrine deficiency. For example, treatment of hypothyroidism with thyroid hormone replacement can precipitate an adrenal crisis in patients with undiagnosed adrenal insufficiency.
Chronic mucocutaneous candidiasis usually requires lifelong antifungal therapy (eg, oral fluconazole or ketoconazole).
Clinical trials of interventions to slow the autoimmune process in type 1 diabetes have shown some promise in delaying the complete destruction of insulin-producing beta-cells. Treatments that have been evaluated include immunotherapy and umbilical cord blood transplantation. Treatments are still experimental (1–3).
Treatment references
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1. Cai J, Wu Z, Xu X, et al: Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: A pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care 39:149–157, 2016.
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2. Haller MJ, Gitelman SE, Gottlieb PA, et al: Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest 125(1):448–455, 2015.
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3. Kroger CJ, Clark M, Ke Q, and Tisch RM: Therapies to suppress β cell autoimmunity in type 1 diabetes. Front Immunol 9:1891, 2018. doi: 10.3389/fimmu.2018.01891
Key Points
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Polyglandular deficiency syndromes involve deficiencies in the function of several endocrine glands, which may occur simultaneously or sequentially.
-
Nonendocrine organs also may be affected.
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Most cases are autoimmune; triggers are often unknown but may involve viruses, dietary substances, or drugs.
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Polyglandular deficiency syndromes are distinguished by the glands affected.
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Treatment involves replacement of deficient hormones.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
ketoconazole |
NIZORAL |
fluconazole |
DIFLUCAN |
